Tuesday, March 18, 2025

TIXIMED Starts a Phase 1 Study of TIX100


TIX100 is a protein which inhibits the action of TIXNP (thioredoxin-interacting protein).  It is being developed by the TIXIMED company.  TXNIP is elevated in pancreatic islets of people with type-1 diabetes and causes beta cell death and dysfunction.  The hope is that inhibiting that protein will protect beta cells and therefore delay or prevent T1D.

Anath Shalev, a researcher at the University of Alabama, Birmingham is leading this research effort, first at UAB and now also at TIXIMED.  She first identified TXNIP in 2002 in human islets exposed to high glucose and then later showed that it played a role in glucose toxicity and diabetic beta cell loss.  Research has shown that inhibiting TXNIP protects beta cells and promotes beta cell health and function.

Recently she has run clinical trials for Verapamil, which lowers TXNIP and is already approved in the USA for the treatment of high blood pressure, migraines, and heart problems.  I have blogged several times on those studies, but especially the results from a phase-II trial here:
I also listed it as a drug to watch in 2024:
because there is another phase-II study ongoing in Europe, but it is now scheduled to finish in 2025 or 2026.

TIX100 is an oral medicine, and a "small molecule", but I have not found any other public information on what it actually is.  It has been tested in animals for T1D, T2D, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).  For example: 
https://diabetesjournals.org/diabetes/article/72/Supplement_1/97-OR/150782/97-OR-Antidiabetic-TIX100-Improves-NAFLD-NASH-in

This Study

This is a blinded dosing study done in healthy people.  They are recruiting 35 people, none of whom have T1D, and giving them 6 different doses ranging from none to 200 mg of TIX100.   The goal is to make sure all potential doses are safe.  

This is a single dose study, follow up is after one week, and they expect to be done by May.  Because the end points are all safety and side effect related, we will not know anything about efficiency (if it actually works against T1D), but "the trip of 1000 miles starts with a single step".  Good results here will presumably enable an efficiency focused phase-II study.

The good things about this study are that it is quick and easy to participate in.  They are recruiting in one location:

Chula Vista, California, United States, 91911
ProSciento, Inc.  619-427-1300   hello@myproscientostudy.com

Corporate Web Page: https://tiximed.com/

To see a longer history of research into curing type-1 diabetes by targeting TIXNP, you can read this article: https://www.news-medical.net/news/20240731/FDA-clears-UAB-startups-TIX100-for-clinical-trials.aspx




Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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Friday, March 7, 2025

Combination of Harmine and GLP-1RA Completes Phase-I Clinical Trial (In Healthy People)

This is the most fun I have had writing a blog in a long time.  It is not often I can blog about psychedelics and curing type-1 diabetes at the same time!  I hope it is as fun for you to read as it is for me to write.  Do not skip the "Discussion" section.

These researchers are testing Harmine as part of a long term project, which started by doing a quick screen of many chemicals, which identified Harmine as a possible way to help the body grow more beta cells.  This screening process involved cell cultures (i.e. biology not computer simulation). They then tested it in mice, and found strong beta cell growth.  They cured the mice of diabetes, but those mice did not have autoimmune diabetes.  Their pancreases were destroyed with a toxin to give them diabetes.  A different research group cured mice who were overfed into diabetes. These are both positive results, but neither involved autoimmune diabetes.

You can read about the mice research here:

This blog reports on their first test in people, but they did not have T1D.  The researchers hope to move on to people with T1D in the future.
  

The Study


This study is unusual in that it enrolled people without T1D ("healthy people", in medical terminology) and only looked for bad side effects ("adverse effects") in the medicine and not effectiveness.  Almost all T1D studies that I've blogged about over more than 10 years, even the earliest phase-I trials enroll people with T1D and have end points that cover both safety and effectiveness.  But not this study.

This is an open-label, no control group, dose escalation study which enrolled 27 people.   Each person goes through the following doses: 100 mg, 200 mg, 300 mg, 500 mg, 700 mg, 900 mg and 1200 mg, stopping when they experience side effects.  The researchers are trying to find the largest does that has minimal side effects.

The results are summarized like this:  Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no adverse effects. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity.   So a 50kg person (110 lb.) can have a dose of 135 mg with minimal adverse effects, and a 91kg / 200 lb. person can go up to 270 mg.

This is good news, because it opens the way for clinical trials on people who have T1D, and tells the researchers what is the maximum dose they can use without bad side effects.


Discussion


Dose Comparison to Mice Work


The important finding of this clinical trial is that doses less than 2.7 mg/kg are safe and well tolerated.  ("well tolerated" being medical jargon for "In our judgement, the side effects of this treatment are small enough so that people would be willing to get them in order to also get the benefits of the treatment".)  For comparison, two previous research projects targeted curing T2D in mice with 30 mg/kg and targeted T1D mice with 3 mg/kg.  Together, this trial in people with T1D and the previous trial in mice suggests that the 3 mg/kg is a "sweet spot" dose: high enough to work and low enough to avoid bad side effects.

However, there was another difference.  People in this study were given Harmine in a single pill, but the previous mice study gave Harmine using a subcutaneous pump (like an insulin pump) and continually dosed throughout the day.  For comparison, the T2D mice were given 30 mg/kg daily with an injection.  So if we compare the people to the T1D mice, they got a similar dose, but the people got it once in a pill and the mice got it infused daily for months.  Since pills are generally easier to take than injections, this is good news, if pills are as effective as injections.

Obviously, an important target of future research is going to be if pills are an effective way of delivering this medicine, or if a continuously dosing pump is required.


Psychedelics


Harmine is found in several species of plants (esp. wild Rue) and animals (esp. butterflies), but it is famous as a component of Ayahuasca, a South American psychoactive folk medicine and religious sacrament.

It is being tested for psychiatric uses (suicide prevention, treating depression, PTSD, etc.) in several clinical trials, some of which have completed and some of which are ongoing.  

My favorite quote is from one of the researchers: 
no psychoactive properties have been identified in animal studies at the doses we are employing, but animals can’t tell you if they’re hallucinating

Obviously, this is why they are carefully doing a phase-I trial on healthy humans, looking specifically for psychedelic adverse effects.  I suspect it is also the reason the study was done at the Depression and Anxiety Center at Mount Sinai Hospital in New York city.  They have more experience with this kind of clinical trial.

I'm sure the association of Harmine with Ayahuasca is going to cause some regulatory complications, even after this study shows that it is not psychoactive at the doses they are giving.  The American DEA has a long history of aggressively opposing any potential medical use associated with psychoactive drugs.  

Wikipedia article on Harmine: https://en.wikipedia.org/wiki/Harmine
Wikipedia article on Ayahuasca: https://en.wikipedia.org/wiki/Ayahuasca

What Next?


In my mind, the obvious next step is to run a phase-I or phase-II trial on people who actually have T1D, but that is not the direction these researchers are going in.  As described below they are looking for a patentable drug (which they hope will be even more effective).

And then there is the issue of bringing these discoveries to people with diabetes. Because harmine is a natural product, it can’t be patented. “If you can’t patent it, no drug company is going to make it because clinical trials are expensive,” he notes.

So, going forward, the team has turned its efforts toward other new small molecule compounds they have designed and synthesized, along with computer modeling. “Some of these are as good as harmine, and several are substantially better. Mount Sinai has patented these, and we’re now working to move them along via Mount Sinai’s Innovation Partners Program,” Dr. Stewart says.

These two paragraphs come from this article:

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here.  I am obese and right on the boarder of T2D and therefore may be taking drugs for those conditions.  My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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Friday, January 31, 2025

Denosumab Starts A Phase-I Trial In People With Established T1D

Denosumab is a monoclonal antibody, which is already approved for several bone related diseases and is sold under the names Wyost, Xgeva, Prolia, and Jubbonti.  A research team has found that the pathway that Denosumab targets also has effects on beta cells. Animal studies suggest that Denosumab may protect and/or increase the number of beta cells and improve how well they work.  It was first approved in 2010 after being developed by Amgen.  There is a biosimilar available from Sandoz.

Denosumab is a subcutaneous (under the skin) injection, much like insulin.  It is taken every month or every six months, depending on the bone disease being treated.

This Study

This is a phase-I trial in 45 adults who have had T1D for between 1 and 5 years. It is blinded, randomized and has a control group.  People will get one injection every 3 months for one year.

There are two primary end points.  For safety, they will track adverse events and for effectiveness they will measure C-Peptide levels. There are secondary end points for more C-Peptide measures and also for A1c measurements.  There are tertiary end points for time-in-range and insulin sensitivity.

The trial started in September 2024 and should run until April 2026.

This study is funded by JDRF and is run out of City Of Hope.  Contact information is:

Name: Arthur Riggs Diabetes & Metabolism Research Institute at COH
Phone: 1-866-44-ISLET(1-866-444-7538)  
Email: Islets@coh.org

And the three sites recruiting are:

University of Alabama-Birmingham Comprehensive Cancer Center
Anath Shalev, MD
205-996-4777 ashalev@uabmc.edu

City of Hope Medical Center, Duarte, California, United States, 91010
Fouad Kandeel, MD, PhD
866-444-7538 Islets@coh.org

Indiana Univ Med Ctr, Indianapolis, Indiana, United States, 46202
Carmella Evans-Molina, MD
317-278-3177 cevansmo@iu.edu

Discussion

This study is being done on people with established T1D, not honeymooners.  However, I'm not sure why.  The researchers state specifically that "Lab studies suggest that Denosumab may protect and/or increase the number of beta cells and improve how well they work."  For me, that suggests that this treatment would work much better during the honeymoon, when people with T1D still have some beta cells that work.  It is a mystery to me why they chose established T1Ds rather than honeymooners.

One large population based study, done in Taiwan, showed that people using Denosumab for Osteoporosis had a significantly smaller chance of being diagnosed with type-2 diabetes, than those who where not taking the drug.  That is an interesting finding, but those people all had plenty of working beta cells, so it is not clear to me that this finding is useful for people with established type-1 diabetes.  That study is published here: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2814873

If this treatment is found effective, it could be used off label immediately, without FDA approval, since it is already approved for a different disease.

Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT06524960 
Denosumab: https://medlineplus.gov/druginfo/meds/a610023.html


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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Sunday, January 19, 2025

What To Watch In 2025

Last year, at the start of the year, I published a blog of four research projects I was looking forward to updates in the new year.  This year, I'm doing the same thing.  I'm also including an update of the project from last year.

What I'm Watching In 2025

Vertex VX-264 is an encapsulated beta cell transplant that does not require immune suppression.  The trial is expected to run until 2026, but the company has said that they expect to have some data to report in 2025.  I hope so!


VCTX211 is another encapsulated beta cell transplant that does not require immune suppression.

Biomea BMF-219 is a drug that the company hopes is "a brake on beta-cell turnover and growth, supporting the notion that [it] could lead to the regeneration of normal, healthy beta cells".  It is in the middle of a clinical trial which started in 2023 and is expected to finish in Sept-2025.  I'm looking forward to data in 2025.  I previously blogged on it here:


Ladarixin is a drug being developed by Dompé. It inhibits activity on parts of the immune system called the IL-8 receptor (which has two subtypes: IL-8a and IL-8b).  Dompé hopes that this will stop the progression of type-1 diabetes.  Ladarixin is in the middle of a phase-III trial, and they expect results in 2025.  This is a big study.  They have enrolled 327 people and 2/3s of them will get the treatment; with only 1/3 controls who get the placebo.


Siplizumab is a monoclonal antibody targeting CD2, which is part of the immune system.  This study finished recruiting in Oct-2024, so I would expect results in late 2025.  I blogged on this here:


Sana UP421 is a last minute addition.  It is a no-immunosuppression beta cell transplant.  In early January, they announced very positive 1 month data from 1 person.  They are currently running a 2 person study (so really tiny pilot study).  I'm not sure if they will have final data in 2025 or not, but if they continue to publish early data, I'll be following.

https://www.clinicaltrials.gov/study/NCT06239636

What I Watched In 2024

The quick summary of 2024, is that, of the four research projects I focused on:
    1. Semaglutide is big in T2D/Obesity, but did not make progress as a T1D cure.
    2. Ladarixin progressed as expected, but the real news is expected in 2025.
    3. Verapamil completed enrollment in 2024, so should have results by 2025, but has already led 
        to important follow-on work.
    4. Diamyd was hoping for full enrollment, but did not make that milestone.
So overall, I would say 1 project did better than expected, 1 project did as expected, and 2 projects did worse.  

Semaglutide (sold as: Ozempic, Wegovy and Rybelsus) had very strong results in a very small study of honeymoon T1Ds:

I was hoping to read about more research starting up in 2024 to confirm these results.  Because Semaglutide is widely used to treat T2D and for weight loss, I think just one or two confirmation studies will be required to enable widespread use.  If that gets us a year or two delay starting injections for newly onset T1D, that would be a huge win (and even more so if it could be combined with Teplizumab or other treatments).

Unfortunately, none of that happened.  Semaglutide continues to blow up (in a good way) for T2D/Obesity, but does not move forward for T1D.

Ladarixin is a drug being developed by Dompé.  I'm not sure why I put it in the 2024 list, because there was no expectation of results until the end of 2025.  Nothing happened, but it is on my 2025 list.


Verapamil is another interesting "off label" drug.  This is a drug which is already approved (since 1981) and widely used (3 million prescriptions a year) for high blood pressure.  It is being tested on honeymooners.  Therefore, if clinical trials show that it helps, it should be available quickly, especially for aggressive doctors who are willing to prescribe it off label.

Unfortunately, the ongoing study which was going to finish in 2024 is now going to finish in either 2025 or 2026, so we'll be waiting longer for results.  I blogged about the start of this study here:

However this line of research has already led to the creation of the company TIXIMED working to start clinical trials on their drug TIX100, which is sort of a follow on to Verapamil.  They have gotten FDA approval for the clinical trial, but have not yet started it.

Diamyd is another drug in phase-III trials.  They hope to finish in 2025, but the news I was hoping for was that their clinical trial was fully enrolled in 2024.  Unfortunately, it looks like that did not happen.  The trial is still not fully enrolled, so I would not expect results in 2025.



Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.
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